JP2005501091A5 - - Google Patents

Claims (26)

Formula I:

[Where
B is, _{H, C 1-6 alkyl,} cycloalkyl of up to _{C 12,} selected aryl of up to _{C 12,} and heteroaryl of up to _{C 12;}
B is independently selected from OH, NO ₂ , CF ₃ , CN, halogen, SC _1-4 alkyl, SOC _1-4 alkyl, SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy Optionally substituted by up to 3 groups;
L ₁ and L ₂ are each independently selected from a direct bond and C _1-6 alkyl;
M ₁ , M ₂ , M ₃ , M ₄ , and M ₅ are each independently selected from N and C;
R1 is -X-Y;
X is C _1-6 alkyl;
Y _is cycloalkyl of up to _{C 10,} the heteroaryl to aryl, and _{C 10} to _{C 10;}
Y is independently selected from OH, NO ₂ , CF ₃ , CN, halogen, SC _1-4 alkyl, SOC _1-4 alkyl, SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy Or optionally substituted with up to 3 groups], or a pharmaceutically acceptable salt thereof or an ester that can be hydrolyzed in vivo. Formula II:

[Where
B is, _{H, C 1-6 alkyl,} cycloalkyl of up to _{C 12,} selected aryl of up to _{C 12,} and heteroaryl of up to _{C 12;}
B is independently selected from OH, NO ₂ , CF ₃ , CN, halogen, SC _1-4 alkyl, SOC _1-4 alkyl, SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy Optionally substituted by up to 3 groups;
L ₁ and L ₂ are each independently selected from a direct bond and C _1-6 alkyl;
M ₁ , M ₂ , M ₃ , M ₄ , and M ₅ are each independently selected from N and C;
R1 is -X-Y;
X is C _1-6 alkyl;
Y _is cycloalkyl of up to _{C 10,} the heteroaryl to aryl, and _{C 10} to _{C 10;}
Y is independently selected from OH, NO ₂ , CF ₃ , CN, halogen, SC _1-4 alkyl, SOC _1-4 alkyl, SO ₂ C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy Or optionally substituted with up to 3 groups], or a pharmaceutically acceptable salt thereof or an ester that can be hydrolyzed in vivo. B is selected from H, C _1-6 alkyl, C ₆ aryl, and heteroaryl up to C ₆ , or a pharmaceutically acceptable salt thereof or in vivo Esters that can be hydrolyzed. B is, H, C _2-4 alkyl, heteroaryl of up to C ₆ aryl, and C _6, hydrolyzed with a compound or a pharmaceutically acceptable salt or in vivo, according to claim 3 Esters that can be made. B is heteroaryl up to C _6, a compound or ester which can be hydrolyzed in a pharmaceutically acceptable salt or in vivo, according to claim 4. Or B is unsubstituted, or is B, CF 3, _CN, halogen, selected from C _1-4 alkyl, which is substituted by at least one group, according to claim 1 or 2 or 3 A compound, or a pharmaceutically acceptable salt or ester that can be hydrolyzed in vivo. At least one of L ₁ and L ₂ is a direct bond, compounds of claim 1 or 2, or an ester which can be hydrolyzed in a pharmaceutically acceptable salt or in vivo,. Ester L ₁ and L ₂ is a direct bond, respectively, which can be hydrolyzed with a compound or a pharmaceutically acceptable salt or in vivo, according to claim 7. The compound according to claim 1, wherein M ₁ is N, or a pharmaceutically acceptable salt thereof or an ester that can be hydrolyzed in vivo. At least one _{M 2, M 3, M 4} , M 5 is is C, and _{M 2,} M _3, M 4, at least one _{M 5} is a N, A compound according to claim 1 or 2, or A pharmaceutically acceptable salt or ester that can be hydrolyzed in vivo. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, or a compound that can be hydrolyzed in vivo, wherein M ₄ and M ₅ are each C and at least one of M ₂ and M ₃ is N ester. M ₂ is C or N, and M ₃ is N, compounds or esters may be hydrolyzed in a pharmaceutically acceptable salt or in vivo, according to claim 11. 3. The compound according to claim 1 or 2, wherein X is _C2-5 alkyl, or a pharmaceutically acceptable salt or ester that can be hydrolyzed in vivo. _14. A compound according to claim 13, or a pharmaceutically acceptable salt or ester that can be hydrolyzed in vivo, wherein X is _C2-3alkyl . Y is C ₆ aryl or C ₆ heteroaryl, esters can be hydrolyzed compound, or a pharmaceutically acceptable salt or in vivo according to claim 1 or 2. 16. A compound according to claim 15, or a pharmaceutically acceptable salt or ester that can be hydrolyzed in vivo, wherein Y is phenyl, pyridyl, pyrimidinyl, or pyrazinyl. 16. A compound according to claim 1 or 2 or 15, or a pharmaceutically acceptable salt thereof or hydrolyzed in vivo, wherein Y is unsubstituted or substituted with at least one halogen. Obtain ester. 2. A compound according to claim 1, or a pharmaceutically acceptable salt or ester that can be hydrolyzed in vivo, wherein the compound of formula I is as exemplified herein. Hydroxy- {1-[({4- [5- (pyridin-2-ylethynyl) pyridin-2-yl] piperazin-1-yl} sulfonyl) methyl] -4-pyrimidin-2-ylbutyl} formamide;
Hydroxy [4-pyrimidin-2-yl-1-({[4- (5-{[5- (trifluoromethyl) pyridin-2-yl] ethynyl} pyridin-2-yl) piperazin-1-yl] sulfonyl } Methyl) butyl] formamide;
Hydroxy {(3S) -3-phenyl-1-[({4- [4- (phenylethynyl) phenyl] piperazin-1-yl} sulfonyl) methyl] butyl} formamide;
Hydroxy [(3S) -3-phenyl-1-({[4- (4-ethynylphenyl) piperazin-1-yl] sulfonyl} methyl) butyl] formamide;
Hydroxy {4-pyrimidin-2-yl-1-[({4- [5- (thien-2-ylethynyl) pyridin-2-yl] piperazin-1-yl} sulfonyl) methyl] butyl} formamide;
1-{[(4- {5-[(4-fluorophenyl) ethynyl] pyridin-2-yl} piperazin-1-yl) sulfonyl] methyl} -4-pyrimidin-2-ylbutyl (hydroxy) formamide;
Hydroxy {(1S) -1-[({4- [5- (pyridin-2-ylethynyl) pyridin-2-yl] piperazin-1-yl} sulfonyl) methyl] -4-pyrimidin-2-ylbutyl} formamide;
Hydroxy {1-[({4- [5- (pyridin-2-ylethynyl) pyrimidin-2-yl] piperazin-1-yl} sulfonyl) methyl] -4-pyrimidin-2-ylbutyl} formamide; and hydroxy {( 1S) -1-[({4- [5- (pyridin-2-ylethynyl) pyrimidin-2-yl] piperazin-1-yl} sulfonyl) methyl] -4-pyrimidin-2-ylbutyl} formamide;
19. A compound according to claim 18 , or a pharmaceutically acceptable salt or ester capable of being hydrolyzed in vivo, selected from: A compound of formula I according to claim 1, or a compound of formula II according to claim 2, or a pharmaceutically acceptable salt or ester which can be hydrolyzed in vivo, and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising A compound of formula I according to claim 1, or a compound of formula II according to claim 2, or a pharmaceutically acceptable salt or in thereof, for use in a method of therapeutic treatment of the human or animal body. Esters that can be hydrolyzed in vivo. A compound of formula I according to claim 1 or a compound of formula II according to claim 2, or a pharmaceutically acceptable salt thereof or an ester that can be hydrolyzed in vivo for use as a therapeutic agent. A method of treating a metalloproteinase-mediated disease or condition, wherein the method comprises treating a warm-blooded animal with a compound of formula I according to claim 1, or a compound of formula II according to claim 2, or a pharmaceutically acceptable salt thereof. Administering a salt or an ester that can be hydrolyzed in vivo in a therapeutically effective amount. 24. A method of treating a metalloproteinase-mediated disease or condition according to claim 23 comprising treating a disease or condition mediated by MMP13. A compound of formula I according to claim 1 or a compound of formula II according to claim 2 or a pharmacology thereof in the manufacture of a medicament for use in the treatment of a disease or condition mediated by one or more metalloproteinases. Use of pharmaceutically acceptable salts or precursors that can be hydrolyzed in vivo. In the manufacture of a medicament for use in the treatment of arthritis, a compound of formula I according to claim 1, or a compound of formula II according to claim 2, or a pharmaceutically acceptable salt thereof or hydrolyzed in vivo Use of precursors that can be decomposed.